Coupling process for generating reactive boron-containing derivatives of N-substituted pyrrole-2-carbonitriles to produce biaryls

ABSTRACT

A convenient preparation of boron-containing compounds, borate salts, pyrrolecarbonitrile boron-containing compounds, N-substituted-pyrrole-2-carbonitrile boron-containing compounds, and derivatives thereof is provided. The present invention also provides for the use of these boron-containing compounds and derivatives thereof in coupling reactions to provide bi-aryl compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the priorities of U.S.Provisional Patent Application No. 60/647,656, filed Jan. 27, 2005 andU.S. Provisional Patent Application No. 60/565,636, filed Apr. 27, 2004.

BACKGROUND OF THE INVENTION

The present invention relates to processes for generatingboron-containing compounds and bi-aryls.

The Suzuki-type coupling to form bi-aryl compounds is usuallyaccomplished by reacting boronic acids with aryl moieties having leavinggroups such as halogen, triflates, and diazonium salts, among others.

In a typical Suzuki coupling, a N-t-butoxycarbonyl-substituted pyrrole(N-Boc-pyrrole) is first deprotonated using butyllithium compounds. Thelithiated N-Boc-pyrrole is then quenched with a trialkylborate,typically triisopropyl borate, and the intermediate reacted with abromoaryl compound in the presence of a palladium catalyst to couple thearyl and pyrrole moieties. Subsequent cyanation of the pyrrole moietyfollowed by Boc deprotection and N-methylation gives the coupledproduct.

This lengthy coupling is plagued by non-selective methylation of thecyano substituent. Further, the intermediates generated during thecoupling have been reported to be thermally unstable.

What is needed in the art are alternative methods for coupling arylcompounds.

SUMMARY OF THE INVENTION

In one aspect, methods for preparing 2-cyanopyrrole boron-containingcompounds are provided.

In a further aspect, methods for preparing 2-cyanopyrrole boronate andborinate salts, boronic and borinic esters and salts thereof, andboronic and borinic acids and salts thereof, are provided.

In another aspect, methods for preparing 2-cyanopyrrole trifluoroboratesalts are provided.

In a further aspect, methods for coupling 2-cyanopyrroles and arylcompounds are provided.

In yet another aspect, the following compounds are provided:

In a further aspect, methods for preparing and purifying5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileare provided.

In still another aspect, methods for preparing and purifying5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileare provided.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for preparing boron-containingcompounds. In one embodiment, the present invention provides methods forpreparing N-substituted pyrrole carbonitrile boron-containing compounds.Such compounds include, without limitation, N-substitutedpyrrole-2-carbonitrile boron-containing compounds,N-alkyl-pyrrole-2-carbonitrile boron-containing compounds, andN-methyl-pyrrole-2-carbonitrile boron-containing compounds.

Such compounds can be isolated or used in situ in further reactions,such as Suzuki-type coupling, to give pyrrole-containing biaryls.

I. Definitions

The term “alkyl” is used herein as a group or part of a group refers toboth straight- and branched-chain saturated aliphatic hydrocarbon groupshaving 1 to about 10 carbon atoms, and desirably 1 to about 8, e.g., 6,carbon atoms. The term “alkenyl” is used herein to refer to bothstraight- and branched-chain alkyl groups having one or morecarbon-carbon double bonds and containing 2 to about 10 carbon atoms.Desirably, the term alkenyl refers to an alkyl group having 1 or 2carbon-carbon double bonds and having 2 to about 6 carbon atoms. Theterm “alkynyl” group is used herein to refer to both straight- andbranched-chain alkyl groups having one or more carbon-carbon triple bondand having 2 to about 8 carbon atoms. Desirably, the term alkynyl refersto an alkyl group having 1 or 2 carbon-carbon triple bonds and having 2to about 6 carbon atoms.

The term “cycloalkyl” is used herein to refer to an alkyl group aspreviously described that is cyclic in structure and has about 3 toabout 10 carbon atoms, e.g., 3-8 carbon atoms, desirably about 5 toabout 8 carbon atoms. The terms “substituted alkyl”, “substitutedalkenyl”, “substituted alkynyl”, and “substituted cycloalkyl” refer toalkyl, alkenyl, and alkynyl groups, respectively, having one or more(e.g., 2 or 3) substituents including, without limitation, halogen, CN,OH, NO₂, amino, aryl, heteroaryl, alkoxy, aryloxy, alkylcarbonyl,alkylcarboxy, and arylthio which groups can be optionally substituted.These substituents can be attached to any carbon of an alkyl, alkenyl,alkynyl, or cycloalkyl group provided that the attachment constitutes astable chemical moiety.

The term “heteroalkyl” is used herein to refer to an alkyl orsubstituted alkyl group as previously described that containsheteroatoms in the backbone of the alkyl moiety. The heteroalkyl hascarbon atoms and one or more heteroatoms including nitrogen, oxygen, andsulfur atoms. Desirably, the heteroalkyl has 1 to about 4 heteroatoms inthe backbone of the ring. The heteroalkyl group typically has 1 to about10 carbon atoms, and desirably 1 to about 8, e.g., 6, carbon atoms.

The term “aryl” as used herein refers to an aromatic system, e.g., ofabout 6-20 carbon atoms, more particularly 6-14 carbons, which caninclude a single ring or multiple (e.g., two or three) aromatic ringsfused or linked together where at least one part of the fused or linkedrings forms the conjugated aromatic system. The aryl groups can include,but are not limited to, phenyl, naphthyl, biphenyl, anthryl,tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, fluorenyl, andcarbazolyl.

The term “substituted aryl” refers to an aryl group which is substitutedwith one or more substituents including halogen, CN, OH, NO₂, amino,alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy,alkylcarbonyl, alkylcarboxy, aminoalkyl, and arylthio, which groups canbe optionally substituted. Desirably, a substituted aryl group issubstituted with 1 to about 4 substituents.

The term “heteroaryl” and “heterocyclic” can be used interchangeably andare used herein to refer to a stable 4- to 20-membered monocyclic ormulticyclic heterocyclic ring which is saturated, partially unsaturated,or wholly unsaturated. Desirably, the monocyclic heterocyclic ring is astable 4- to 7-membered ring. The heteroaryl or heterocyclic ring hascarbon atoms and one or more heteroatoms including nitrogen, oxygen, andsulfur atoms. Desirably, the heteroaryl or heterocyclic ring has 1 toabout 4 heteroatoms in the backbone of the ring. When the heteroaryl orheterocyclic ring contains nitrogen or sulfur atoms in the backbone ofthe ring, the nitrogen or sulfur atoms can be oxidized. The term“heteroaryl” or “heterocyclic” also refers to multicyclic rings in whicha heteroaryl or heterocyclic ring is fused to an aryl ring. Theheteroaryl or heterocyclic ring can be attached to the aryl ring througha heteroatom or carbon atom provided the resultant heterocyclic ringstructure is chemically stable.

A variety of heteroaryl or heterocyclic groups are known in the art andinclude, without limitation, oxygen-containing rings,nitrogen-containing rings, sulfur-containing rings, mixedheteroatom-containing rings, fused heteroatom containing rings, andcombinations thereof. Oxygen-containing rings include, but are notlimited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinylrings. Nitrogen-containing rings include, without limitation, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, pyridyl, piperidinyl,2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfur-containingrings include, without limitation, thienyl and dithiolyl rings. Mixedheteroatom containing rings include, but are not limited to, oxathiolyl,oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, anddiazepinyl rings. Fused heteroatom-containing rings include, but are notlimited to, benzofuranyl, thionapthene, indolyl, benazazolyl,purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl,anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl, benzodiazonyl,napthylridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl, xanthenyl,acridinyl, and purinyl rings.

The term “substituted heteroaryl” or “substituted heterocyclic” as usedherein refers to a heteroaryl or heterocyclic group having one or moresubstituents including halogen, CN, OH, NO₂, amino, alkyl, cycloalkyl,alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl,alkylcarboxy, aminoalkyl, and arylthio, which groups can be optionallysubstituted. Desirably, a substituted heteroaryl or heterocyclic groupis substituted with 1 to about 4 substituents.

The term “alkoxy” as used herein refers to the O(alkyl) group, where thepoint of attachment is through the oxygen-atom and the alkyl group isoptionally substituted.

The term “aryloxy” as used herein refers to the O(aryl) group, where thepoint of attachment is through the oxygen-atom and the aryl group isoptionally substituted.

The term “alkyloxy” as used herein refers to the alkylOH group, wherethe point of attachment is through the alkyl group and the alkyl groupis optionally substituted.

The term “arylthio” as used herein refers to the S(aryl) group, wherethe point of attachment is through the sulfur-atom and the aryl group isoptionally substituted.

The term “alkylcarbonyl” as used herein refers to the C(O)(alkyl) group,where the point of attachment is through the carbon-atom of the carbonylmoiety and the alkyl group is optionally substituted.

The term “alkylcarboxy” as used herein refers to the C(O)O(alkyl) group,where the point of attachment is through the carbon-atom of the carboxymoiety and the alkyl group is optionally substituted.

The term “aminoalkyl” as used herein refers to both secondary andtertiary amines where the point of attachment is through thenitrogen-atom and the alkyl groups are optionally substituted. The alkylgroups can be the same or different.

The term “halogen” as used herein refers to Cl, Br, F, or I groups.

The term “acyl” as used herein refers to an alkyl or substituted alkylgroup as just described having a carbonyl group, i.e., C(═O) group, inthe backbone of alkyl moiety.

The term “sulfonyl” as used herein refers to an alkyl or substitutedalkyl group as just described having a sulfonyl group, i.e., SO₂ groupin the backbone of the alkyl moiety.

The term “leaving group” as used herein refers to a substituent that ispresent on a chemical compound and can be displaced (the term L as usedherein refers to a leaving group). The particular leaving group utilizedin the present invention is dependent upon the specific reaction beingperformed and can readily be determined by one of skill in the art.Common leaving groups include, without limitation, halides andsulfonates (OSO₂R), whereby R′ is an alkyl. Desirably, the leaving groupis a halide such as bromine, chlorine, or iodine, and more desirably isbromine.

The term “organometallic coupling agent” as used herein refers tocompound that contains a transition metal and one or more ligandsattached thereto. A variety of transition metals can be used in thepresent invention and include Pd and Ni metals, among others. Severalligands can be bound to the transition metal and include, withoutlimitation, acetate, hydroxyl, nitrile, halide, and phosphinesubstituents. Many transition metal complexes containing such ligandsare commercially available and include those recited on the StremChemical, Inc. website. Desirably, the organometallic coupling agent isselected from among tetrakis(triphenylphosphine)palladium,Bis(tri-tert-butylphosphine)palladium(0),Tris(dibenzylideneacetone)dipalladium(0),Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II),trans-Dichlorobis(triphenylphosphine)palladium(II),Palladium(II)acetate, Palladium(II)chloride, Palladium on carbon,Dichloro[1,1′-bis(diphenylphosphino)ferrocene]nickel(II), andBis(triphenylphosphine)nickel(II) chloride.

As used herein, the term “strong non-nucleophilic base” refers to acompound that is capable of removing a H-atom attached to a carbon-atom(designated CC⁺base in the description and schemes). Desirably, thestrong non-nucleophilic base can remove a H-atom from a pyrrole ring,but not react with the other substituents on the ring, if so present.Desirably, the strong non-nucleophilic base can remove a H-atom from the5-position of a pyrrole ring. A variety of strong non-nucleophilic basesis known to those of skill in the art and include diisopropyl aminesalts. See, the strong non-nucleophilic bases on the FMC Lithiumwebsite. In one embodiment, the strong nucleophilic base is lithiumdiisopropyl amide (LDA).

The term “boron agent” as used herein refers to a neutral compound thatcontains a boron atom (designated BR₃ or B(O-subst)₃ in the schemes).Typically, the boron agent has 1, 2, or 3 substituents. Desirably, thesubstituents (abbreviated “subst” herein and in the schemes) are bounddirectly to the boron atom or through an O-atom.

The term “borate salt” as used herein refers to a compound containing aboron atom and is present as a salt including boronate and borinatesalts. Derivatives of borate salts include, without limitation, bothneutral and charged compounds including boronic esters, borinic esters,boronic acids, or borinic acids.

The term “boronate ester salt” as used herein refers to a compoundhaving a —B(O-substituent)₃ or —B(substituent)₃ group attached thereto,wherein the substituent forms a stable bond. The term “boronate ester”also refers to a compound having the a —B[—O—R¹⁹—O—] group attachedthereto, wherein the boron atom is bound to the compound and to the twoO-atoms, where R¹⁹ is defined below.

The term “borinate ester salt” as used herein refers to a compoundhaving a —B(O-substituent)₂— or —B(substituent)₂— group attachedthereto, wherein the substituent forms a stable bond to an O-atomattached to the boron atom and the boron atom is attached to thecompound through 2 bonds.

The term “boronic ester” as used herein refers to a compound having a—B(O-substituent)₂ group attached thereto, wherein the substituent formsa stable bond to an O-atom attached to the boron atom. The term “boronicester” also refers to a compound having a —B[—O—R¹⁹—O—] group attachedthereto, wherein the boron atom is bound to the compound and to the twoO-atoms, where R¹⁹ is defined below.

The term “borinic ester” as used herein refers to a compound having a—B(O-substituent)- group attached thereto, wherein the substituent formsa stable bond to an O-atom attached to the boron atom and the boron atomis attached to the compound through 2 bonds.

The term “boron compound” as used herein refers to a neutral compoundprepared according to the present invention having a —B(substituent)₂ or—B(substituent)- group attached thereto, wherein the substituent forms astable bond to the boron-atom.

The term “boronic acid” as used herein refers to a compound having a—B(OH)₂ group attached thereto.

The term “borinic acid” as used herein refers to a compound having a—B(OH)— group attached thereto and the boron atom is attached to thecompound through 2 bonds.

The term “catalyst scavenger” as used herein refers to a compound orcomplex that removes a catalyst from a solution containing the catalyst.

II. Methods of Preparing Boron-Containing Compounds and DerivativesThereof

The present invention provides methods for preparing boron-containingcompounds which can be isolated or used in situ in further reactions.These boron-containing compounds, and derivatives thereof, are definedin detail above and include boronate salts, borinate salts, boronicesters and salts thereof, borinic esters and salts thereof, boronicacids, and borinic acids.

In one embodiment, boronic and borinic esters of formulas (A) and (B)can be prepared according to the invention.

Certain boron compounds can be prepared according to the presentinvention and include compounds of formulas (C) and (D).

Salts of the boronic and borinic esters and the boron compounds can alsoindependently be prepared according to the present invention and are offormulas (E), (F), (G), or (H).

In one embodiment, R¹, R², and R³ are selected from among C₁ to C₆alkyl, C₃ to C₈ cycloalkyl, and hetero(C₁ to C₆)alkyl. Desirably, R¹,R², and R³ are isopropyl.

In a further embodiment, the following 2-cyanopyrrole boron-containingcompounds are prepared according to the present invention. In thesecompounds, CC⁺ denotes a countercation from the strong non-nucleophilicbase that interacts with the base molecule to form a stable compound andQ, a, R⁷, subst, and CC⁺ are defined above.

In another embodiment, the following 2-cyanopyrrole boronic esters,boronic ester salts, borinic esters, or borinic ester salts are preparedaccording to the present invention.

The methods for preparing boron-containing compounds, such as boronateand borinate salts, include combining a boron agent, an optionallysubstituted cyanopyrrole, and a strong non-nucleophilic base. See,Scheme 1, where R, subst., R⁷, Q, a, and CC⁺ are defined above or below.

In one aspect, the boron agent is of the formula B(OR¹)(OR²)(OR³)(depicted as B(O-subst)₃ for convenience in Scheme 1 above). R¹, R², andR³ are, independently, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ toC₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, heteroaryl, substitutedheteroaryl, hetero(C₁ to C₆)alkyl, or substituted hetero(C₁ to C₆)alkyl.In one embodiment, R¹, R², and R³ are C₁ to C₆ alkyl. In a furtherembodiment, R¹, R², and R³ are isopropyl. In yet a further embodiment,R¹, R², and R³ are C₃ to C₈ cycloalkyl. In still another embodiment, oneor more of R¹, R², or R³ are hetero(C₁ to C₆)alkyl and comprise oxygenatoms. In yet a further embodiment, R¹, R², or R³ are, independently,CH₂CH₂—O—R²³, where R²³ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl,aryl, substituted aryl, or heteroethyl groups such as—CH₂CH₂(O—CH₂CH₂—O)_(m)CH₂CH₃ and m is 1 to 8.

In another embodiment, the boron agent is of the formula B(R⁴)(R⁵)(R⁶),wherein R⁴, R⁵, and R⁶ are, independently, halogen, C₁ to C₆ alkyl, orsubstituted C₁ to C₆ alkyl. This is depicted as BR₃ in the above-notedScheme 1 for convenience.

Numerous cyanopyrroles can be used in the present invention and includeN-substituted cyanopyrroles. In one embodiment, N-substituted2-cyanopyrroles are utilized in the present invention. In anotherembodiment, N-alkyl-2-cyanopyrroles are utilized in the presentinvention. In a further embodiment, N-methyl-2-cyanopyrroles areutilized in the present invention.

In one embodiment, a cyanopyrrole of the following structure can beutilized.

In formula I, R⁷ is selected from among C₁ to C₆ alkyl, substituted C₁to C₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,or COR^(A). R^(A) is selected from among H, C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl. Q is selected from amongH, OH, NH², CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl,substituted C₂ to C₆ alkynyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆ aminoalkyl, or COR^(B)and a is 0, 1, or 2. R^(B) is selected from among H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl. In oneembodiment, the cyanopyrrole is 1-methyl-pyrrole-2-carbonitrile

The strong non-nucleophilic base must be sufficiently reactive to removea hydrogen-atom from the pyrrole ring of the cyanopyrrole, but not reactwith the other substituents of the ring. A number of strongnon-nucleophilic bases are known in the art and include those recitedabove. In one embodiment, the strong non-nucleophilic base is a lithiumagent, which is desirably selected from among lithium amine salts. Inone embodiment, the lithium amine salt is a dialkyl lithium amine salt,and in another embodiment, diisopropyl lithium amide (LDA).

The 2-cyanopyrrole boron-containing compounds, or derivatives thereof,are typically prepared in a solvent. Any solvent that does not reactwith the boron agents, the optionally substituted cyanopyrrole, strongnon-nucleophilic base, or cyanopyrrole boron-containing compounds, orderivatives thereof, can be utilized. The solvent is desirablydehydrated, but can contain small amounts of water. Typically, thesolvent includes an ether such as tetrahydrofuran (THF), diethylether,or combinations thereof in non-ether solvents. In one embodiment, theether is THF or a combination of THF/heptane/ethylbenzene.

The amount of solvent utilized depends upon the scale of the reactionand the amounts of 2-cyanopyrrole, boron agent, and strongnon-nucleophilic base. One of skill in the art would readily be able todetermine the amount of solvent required to prepare the 2-cyanopyrroleboron-containing compounds.

III. Methods for Preparing Boronic or Borinic Acids or DerivativesThereof

The present invention also provides for preparing derivatives of theborate salts including boronic acids, borinic acids, cyanopyrroleboronic acids, and cyanopyrrole borinic acids. Such boronic and borinicacids are typically isolated in situ and utilized in further reactions.

Typically, the boronic acids and borinic acids are present as a mixtureof the boronic and borinic acid, optionally in the presence of residualboronic ester or salt thereof or borinic ester or salt thereof. Thecomposition of the boronic acid/borinic acid mixture depends on thereaction conditions and can be determined by techniques known to thoseof skill in the art including liquid chromatography and or mass spectralanalysis. For example, one mixture prepared according to the presentinvention contained 79.2% borinic ester (exact mass 280), 19.0% borinicacid (exact mass 238) and 1.9% boronic acid (exact mass 150).

The boronic and borinic acids can be prepared using the boronic and/orborinic esters or salts thereof as described above and hydrolyzing thesame. See, Schemes 2 and 3, where CC⁺, subst, Q, a, and R⁷ are definedherein. Typically, hydrolyzing is accomplished using water which maycontain other components including acids such as hydrochloric acid.

In one embodiment, the following cyanopyrrole boronic and borinic acidsare prepared according to the present invention, where Q, a, and R⁷ aredefined above.

In another embodiment, the following cyanopyrrole boronic and borinicacids are prepared according to the present invention.

The inventors have found that cyanopyrrole boronic acid compounds can beunstable. However, without wishing to be bound by theory, the inventorshave found that the formation of a boronate ester from the boronic acidstabilizes the compound, thereby permitting storage of the resultingcompound at room temperature. The inventors have also hypothesized thatthe stability of the boronate ester can be due to the presence of anoptional N-atom in the boronate ester.

The present invention therefore provides boronate esters and methods forpreparing them from boronic acids. In one embodiment, the followingboronate esters are prepared according to the present invention.

where, R¹⁸ is selected from among 2-cyanopyrrole or substituted2-cyanopyrrole; R¹⁹ is selected from among (CR²⁰R²¹), or—(CR²⁰R²¹)_(s)—N(R²²)—(CR²⁰R²¹)_(t)—; s is 1, 2, 3, 4, or 5; and t is 1,2, 3, 4, or 5. R²⁰ and R²¹ are, independently, selected from among H, C,to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, and substituted aryl. R²²is selected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂to C₆ alkenyl, substituted C₂ to C₆ alkenyl, aryl, and substituted aryl.Desirably, R¹⁹ is —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—,—C(CH₃)₂CH(CH₃)—, or —C(CH₃)₂C(CH₃)₂—. When R¹⁹ is—(CR²⁰R²¹)_(s)—N(R²²)—(CR²⁰R²¹)_(t)—, R²⁰ and R²¹ are desirably H, R²²is desirably H, phenyl, or methyl, s is 2, t is 2, and R¹⁸ isN-methyl-2-pyrrole carbonitrile. R²² is more desirably H.

The boronate esters are prepared according to the present invention byreacting a boronic acid with a glycol or alkanolamine. See, Scheme 4.

In one embodiment, the boronate ester is prepared by reacting a boronicacid with a glycol including HO—CR²⁰R²¹—OH. See, Scheme 5. A variety ofglycols can be utilized to prepare the boronate esters and include,without limitation, those of the formula HO—CR²⁰R²¹—OH, where R²⁰ andR²¹ are defined above. Desirably, the glycol is 1,3-propylenediol,1,2-propylenediol, 1,2-butylenediol, 1,2-pentylenediol, or1,2-hexylenediol.

In another embodiment, the boronate ester is prepared by reacting aboronic acid with a dialkanolamine including, without limitation,HO—CR²⁰R²¹—N(R²²)—CR²⁰R²¹—OH, where R²⁰, R²¹, and R²² are defined above.See, Scheme 6. Desirably, the dialkanolamine is diethanolamine.

In one embodiment, the boronate ester5-[1,3,6,2]Dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile isprepared according the present invention. See, Scheme 7, where R⁷,subst, R¹⁹, and CC⁺ are defined above.

IV. Methods of Preparing Trifluoroborate Salts

The present invention further provides methods for preparingtrifluoroborate salts and cyanopyrrole trifluoroborate salts bycombining a fluoride agent with a boronic ester, borinic ester, or saltthereof as described above.

A number of fluoride agents can be utilized to prepare thetrifluoroborate salts and include reagents such as hydrogen fluoride, orderivatives thereof including potassium hydrogen fluoride, among others.One of skill in the art would readily be able to determine a suitablefluoride agent to utilize in the present invention.

In one embodiment, the following trifluoroborate salt is preparedaccording to the present invention.

V. Methods for Coupling Boron-Containing Compounds and Aryl Compounds

The present invention further provides methods for coupling arylcompounds. The present invention specifically provides for coupling anaryl compound with a cyanopyrrole, and more specifically, coupling arylcompounds with cyanopyrrole boronate and borinate salts, boronic andborinic esters of salts thereof, or boronic and borinic acids as justdescribed.

Such couplings can be performed with or without isolation of thecyanopyrrole boron-containing salts. Desirably, the cyanopyrroleboron-containing salts are not isolated and are utilized in situ in thecoupling reaction.

Typically, a cyanopyrrole boron-containing salt as previously describedis combined with an aryl compound and an organometallic coupling agent.

A variety of aryl compounds can be used in the present invention andinclude aryl compounds having a leaving group (L) attached to acarbon-atom of the aryl ring. In one embodiment, the aryl compounds havethe following structure:

R⁸ and R⁹ are independently selected from among H, C₁ to C₆ alkyl, orsubstituted C₁ to C₆ alkyl; or R⁸ and R⁹ are fused to form a saturated 3to 8 membered spirocyclic ring, a 3 to 8 membered spirocyclic ringhaving in its backbone at least 1 carbon-carbon double bond, or a 3 to 8membered heterocyclic ring containing in its backbone 1 to 3 heteroatomsselected from among O, S and N. These rings are optionally substitutedby from 1 to 4 groups selected from among fluorine, C₁ to C₆ alkyl, C₁to C₆ alkoxy, C₁ to C₆ thioalkyl, CF₃, OH, CN, NH², NH(CL to C₆ alkyl),or N(C₁ to C₆ alkyl)₂. R¹⁰ is selected from among H, OH, NH₂, CN,halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, or CORD. RD is selected from among H, C, to C₆ alkyl,substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C, to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl. R¹¹ isselected from among H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ toC₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, orsubstituted C₁ to C₆ aminoalkyl. L is selected from among halogen,triflate, or a diazonium salt; G is selected from among O, S, or absent;and D is selected from among O, S, NR¹², or CR¹³R¹⁴. R¹² is selectedfrom among CN, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, SO₂CF₃, OR¹⁵ or NR¹⁵R¹⁶. R¹³ and R¹⁴are, independently, selected from among H, C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, NO₂, CN, orCO₂R¹⁷; R¹⁵ and R¹⁶ are, independently, selected from among H, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, acyl or sulfonyl; R¹⁷ is C₁ to C₃ alkyl; orCR¹³R¹⁴ is a six membered ring as shown by the structure below:

or a pharmaceutically acceptable salt thereof. Desirably, L is halogen,and more desirably L is bromine or iodine.

In a further embodiment, aryl compounds of the following structure areemployed in the present invention, where R⁸-R¹¹, L, G, and D are definedabove.

In another embodiment, aryl compounds of the following structures areused, where D and halogen are defined above.

In a further embodiment, aryl compounds of the following structures areused, where D is defined above.

In yet another embodiment, aryl compounds of the following structuresare used.

The coupling of the present invention is typically carried out in acoupling solvent. Any coupling solvent that permits coupling of the arylcompounds can be utilized and desirably includes solvents that dissolveone or more of the organometallic coupling agent, 2-cyanopyrroleboron-containing compound, and aryl compound. Desirably, the couplingsolvent is maintained at about room temperature or below. The solvent isdesirably dehydrated, but can contain small amounts of water. Typically,the solvent includes an ether such as THF, diethylether, andcombinations thereof, and is desirably THF.

The amount of solvent utilized depends upon the scale of the reactionand specifically the amount of organometallic coupling agent,2-cyanopyrrole, and aryl compound present in the reaction mixture. Oneof skill in the art would readily be able to determine the amount ofsolvent required to perform the coupling.

The solvent can also optionally contain additional components that donot interfere with the coupling. One of skill in the art would readilybe able to determine if an additional component is adverse to thecoupling reaction.

In one embodiment, the following compounds can be prepared according tothe invention, where R⁷-R¹¹, Q, a, D, and G are defined above.

In another embodiment, the following compounds can be prepared accordingto the invention, where R⁸-R¹¹, G, and D are defined above.

In a further embodiment, the following compounds can be preparedaccording to the invention, where R⁸-R¹⁰ are defined above.

In yet another embodiment, the following compounds can be preparedaccording to the invention.

In still a further embodiment,5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileis prepared according to the present invention. This process includesreacting 1-methyl-pyrrole-2-carbonitrile and a boron agent; coupling theboronated carbonitrile with6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoazin-2-one (the Brofoxine™reagent) to give5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.See, Scheme 8. Desirably, the boron agent is tri-isopropylborate. Theboron agent is typically reacted with the carbonitrile in the presenceof lithium di-isopropylamide (LDA) and tri-isopropylborate to give aboronate/borinate mixture which is not isolated. The coupling istypically performed in situ in the presence of a soluble palladium (0)catalyst to give5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrilein an unpurified form.

In yet another embodiment,5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileis prepared by reacting 1-methyl-pyrrole-2-carbonitrile, a slight excess(about 1.3 equivalents) of lithium di-isopropylamide (LDA) andtri-isopropylborate in tetrahydrofuran (THF) at a reduced temperature ofabout −2 to about 8° C. to give a boronate/borinate mixture. Thismixture is then treated in situ with a limiting amount (about 1equivalent) of the Brofoxine™ reagent, potassium carbonate, andtetrakis(triphenylphosphine) palladium in THF at elevated temperatures,desirably not exceeding about 70° C. to give5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrilein an unpurified form.

The present invention also provides a purified form of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileproduct. The purified form is typically prepared by adjusting the pH ofthe THF solution containing the5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileto about 4 to about 5; removing residual palladium catalyst in the THFsolution using a catalyst scavenger; removing the catalyst scavenger;exchanging the THF for a second solvent; concentrating the secondsolvent; precipitating the purified product; slurrying the precipitatedproduct; and drying the purified product. See, Scheme 9. Typically, thecatalyst scavenger reacts with the catalyst. In one embodiment, thecatalyst scavenger is cysteine.

In one embodiment, purification of5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileproduct includes washing the unpurified product with water and THF andcooling the same, desirably to 19 to 25° C.; adjusting the pH of thewashed product to 4 to 5 using an acid such as hydrochloric acid or abase such as sodium hydroxide, desirably maintaining the temperature at5 to 15° C., warming to about room temperature, and removing the aqueousphase; removing residual palladium catalyst from the organic phase,typically by adding L-cysteine and heating the mixture, desirably to 49to 55° C.; removing excess cysteine by a route such as filtration;exchanging the solvent for toluene, desirably by distillation;concentrating the toluene solution; precipitating the product usingheptane; collecting the purified precipitated product; slurrying theprecipitated product in methanol; and drying the purified product,desirably at a temperature less than about 45° C.

In yet another embodiment,5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileis prepared according to the present invention. Specifically,5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileis converted to the corresponding thioxo compound by reacting5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrilewith Lawesson's reagent. See, Scheme 10.

In one embodiment,5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileis prepared by reacting5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrilewith Lawesson's reagent (about 1.1 equivalents), 1,2-dimethoxyethane(DME), and acetonitrile. Desirably, the reaction is performed atelevated temperatures such as 85 to 89° C. Typically, this reaction ispermitted to progress for no more than 16 hours.

The present invention also provides for purifying5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.The purification includes forming a salt of the product; acidifying thesalt; and isolating the acidified product, i.e., purified5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.See, Scheme 11.

In one embodiment, purification of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrileincludes quenching the thionation reaction with water, desirably at atemperature of about 18 to 28° C. and for at least 2 hours, slurryingthe solid in water, and drying the slurried product under vacuum,desirably at room temperature for at least 12 hours; reacting the driedthioxo compound with potassium t-butoxide, desirably at 10 to 20° C. forat least 1 hour, to form the potassium salt of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile;acidifying the potassium salt with hydrochloride acid/acetone/water,desirably at 2 to 8° C. for at least 80 minutes, to a pH of 3 to 5;dissolving the acidified salt in acetone with heating, desirably to 45to 51° C., filtering the solution, and heating the filtered solution toreflux, precipitating solid from the heated solution with water andcooling, desirably to 2 to 8° C., and isolating the same; washing theisolated product with acetone/water; and drying the purified product ata temperature of about 35° C. and then at a temperature of less than 45°C.

VI. Reagents of the Invention

The compounds of the present invention, including(5-cyano-1-methyl-1H-pyrrol-2-yl) boronic acid,(5-cyano-1-methyl-1H-pyrrol-2-yl) trifluoroborate potassium salt, and5-[1,3,6,2]Dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile areuseful in a variety of reactions known to those of skill in the art andinclude those described in U.S. Pat. Nos. 6,509,334; 6,566,358;6,391,907; 6,436,929; 6,407,101; and 6,562,857, which are hereinincorporated by reference. Desirably, these compounds are useful incoupling reactions.

The compounds of the invention can be premixed in a solvent, providedthat the solvent does not substantially degrade or decompose thecompound, and bottled in a suitable container or kit, such as are knownin the art.

Alternatively, the invention provides a container or kit whereby thecompounds of the present invention are provided in a container. Suchcontainers or kits can include the compound as a solid and optionalseparate aliquot of solvent required for dissolution of the solidcompound.

The following examples are provided to illustrate the invention and donot limit the scope thereof. One skilled in the art will appreciate thatalthough specific reagents and conditions are outlined in the followingexamples, modifications can be made which are meant to be encompassed bythe spirit and scope of the invention.

EXAMPLES EXAMPLE 1 Preparation of the Boron Containing Compounds

A. The Boronate Mixture

To a 3-L flask equipped with nitrogen inlet, pump inlet, overheadstirrer, temperature controller and a cooling bath were charged1-methylpyrrole-2-carbonitrile (99 g, 0.933 mol), triisopropylborate(176 g, 216 mL, 0.936 mol), and THF (600 mL). After cooling the solutionto about 0° C., 2M LDA (606 mL, 1.21 mol) was added in small portions,via a pump, at the rate of about 2.5 mL/min. The bath was removed andthe suspension was stirred for about 1 hour at about 15° C.

B. The Trifluoroborate Salt

The boronate mixture (16 mL) prepared as described above was stirredwith 5M aqueous sodium hydroxide (NaOH; 15 mL) for about 30 minutes thenacidified with 10% aqueous hydrochloric acid (HCl) to a pH of about 2.Extraction with ethyl acetate and evaporation to dryness left a residuethat was dissolved in methanol (MeOH; 5 mL) and treated with potassiumhydrogen fluoride (KHF₂; 0.77 g) in water (10 mL). After stirringovernight, the yellow mixture was evaporated to dryness and extractedwith hot acetone. A white precipitate was formed upon addition of ether,which was thereby filtered, washed with ether and dried to give 0.5 g of(5-cyano-1-methyl-1H-pyrrol-2-yl) trifluoroborate potassium salt. ¹H-NMR(acetone-d₆): δ 6.58, 6.01, and 3.74. ¹⁹F-NMR (acetone-d₆): 6-141.

C. The Boronic Acid

The solution of 1-methylpyrrole-2-carbonitrile (0.131 g, 1.23 mmol),triisopropylborate (250 μL, 1.08 mmol), and THF (4 mL) was cooled toabout −4° C. and 2M LDA (0.6 mL, 1.2 mmol) was added dropwise from asyringe. The bath was removed and the suspension was allowed to warm toabout 13° C. within about 2 hours. After cooling and quenching withwater and 5% aqueous HCl, the product was extracted with diethylether.The organic layer was evaporated to give an oil which solidified uponstanding to give 0.130 g (70% yield) of(5-cyano-1-methyl-1H-pyrrol-2-yl) boronic acid. ¹H-NMR (DMSO-d₆): δ8.38, 6.87, 6.77, and 3.88.

D. Diethanolamine Ester

A 5-L flask was charged with a 2M LDA solution (800 mL, 0.16 mol) andcooled to 0 to 5° C. In a separate flask, 1-methylpyrrole-2-carbonitrile(100 g, 0.99 mol) was mixed with triisopropylborate (178 g, 0.99 mol)and diluted with THF (1 L). This solution was added into LDA over aperiod of 5 hours, maintaining the temperature at 0 to 5° C. Uponcompletion of the reaction, 4N HCl and brine (1 L, each) were addeddropwise maintaining temperature at 10° C. The phases were separated andthe organic phase was stirred with diethanolamine (180 g, 1.7 mol) for 1hour. The THF was evaporated and the residue triturated with isopropanol(1 L) and the solvent was evaporated to approx. 500 mL. The resultantslurry was stirred for 30 minutes at 0 to 5° C., filtered, washed withcold isopropanol (200 mL and 100 mL) and dried in a vacuum-oven at 45°C. to give5-[1,3,6,2]dioxazaborocyan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile (155g, 75% yield). ¹H NMR (DMSO-d₆): 7.22, 6.73, 6.125, 3.9-3.75, 3.72,3.17-3.09, and 2.9-2.8.

EXAMPLE 2 SCALE-UP PREPARATION OF5-[1,3,6,2]DIOXAZABOROCAN-2-YL-1-METHYL-1H-PYRROLE-2-CARBONITRILE

In this example, a larger scale production of5-[1,3,6,2]dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile wasperformed using the procedure of Example 1D.1-Methylpyrrole-2-carbonitrile (6.01 kg, 56.6 mol) and triisopropylborate (10.7 kg, 56.9 mol) were dissolved in tetrahydrofuran (48 kg).The solution was transferred into a reactor containing pre-cooled to −2°C. 2.0 M lithium diisopropylamide in heptane, ethylbenzene and THF (39.3kg, 96.8 mol). The addition was performed over 3 hours and the reactiontemperature was controlled in the range of −5 to 5° C. Following a holdof at least 30 minutes at 0 to 10° C., the batch was sampled forreaction completion analysis by high performance liquid chromatography(HPLC). Residual starting material was analyzed at 0.28%.

The reaction mixture was quenched with 4N HCl (65 kg) between 0 and 15°C. To achieve good phase separation, 18% sodium chloride brine solution(68 kg) was added, the mixture was stirred at 16 to 21° C. for an hour,then allowed to settle for 20 minutes. The lower aqueous phase wasdrained into a drum and diethanolamine (10.9 kg, 104 mol) was added tothe organic phase over 30 minutes. A large amount of the solvent wasremoved by vacuum distillation at about 160 mm Hg absolute pressure anda batch temperature range of 30 to 37° C. Isopropanol (47 kg) was addedto the concentrate as a replacement solvent for THF and for productcrystallization. The reactor was heated back up and the process mixtureconcentrated to the same volume endpoint by vacuum distillation at about110 mm Hg absolute pressure and 38 to 43° C. The concentrate was cooledto 25° C. and the resulting slurry was filtered. The cake was washedwith cold isopropanol (24 kg) and dried with a nitrogen purge. The cakewas further dried under vacuum at 45° C. to give 8.27 kg (66.7% yield)of the product.

EXAMPLE 3 Coupling Using the Boronate Salt Mixture

A 5-L, 4-necked flask equipped with nitrogen inlet, overhead stirrer,reflux condenser, pump inlet and temperature controller was charged withTHF (600 mL), the Brofoxine™ reagent (128 g, 0.500 mol), solution ofpotassium carbonate (132 g, 0.955 mol) in water (460 mL), andtetrakis(triphenylphosphine)palladium (1.2 g, 0.001 mol). The suspensionwas heated to about 65° C. and the boronate mixture of Example 1 wasadded in small portions at a rate of about 5 mL/min. The reactionmixture was cooled to about 10° C. and treated, in small portions, withconcentrated HCl (300 mL) to a pH of about 4 to about 5. Water (1.0 L)was added and the phases were separated. The organic phase was dilutedwith THF (300 mL). The Darco® KB clearing aid (12.0 g) was added and themixture was filtered through a pad of the Celite® reagent. After washingthe cake with THF (300 mL), the filtrate was distilled under vacuum toabout one-fourth of the original volume (about 0.7 L). Toluene chaseleft a yellow suspension. Heptane (1.0 L) was added to completeprecipitation of the yellow solid. The solids were filtered, washed withmother liquor and slurried in methanol (200 mL). Filtration, followed bydrying gave the desired product (120 g, 85% yield, purity 98.8% HPLCarea, mp 222.8° C.).

EXAMPLE 4 Coupling Using the Trifluoroborate Salt

5-Bromo-(spiro[cyclohexane-1,3′-[3H]indol])-2′-ylidene-cyanamide (3.0 g,9.86 mmol), the trifluoroborate salt (2.1 g, 9.90 mmol) prepared asdescribed in Example 1, potassium carbonate (4.2 g, 30 mmol), andtetrakis(triphenylphosphine) palladium (24 mg) are refluxed in water (5mL) and THF (10 mL) for about 11 hours. The reaction mixture is cooledto ambient temperature, quenched with water and acidified with HCl to apH of about 3. The solids are filtered, washed with water, isopropanoland dried to give5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-spiro[cyclohexane-1,3′-[31H]indol]-2′-ylidene-cyanamide.

EXAMPLE 5 Coupling Using the Diethanolamine Ester

A 3-L flask was charged with5′-bromospiro[cyclohexane-1,3′-indol]-2′(1′H)-one (100 g, 0.357 mol),DME (750 mL), and a solution of potassium carbonate (99 g, 0.713 mol) inwater (0.5 L).5-[1,3,6,2]Dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile (118g, 0.536 mol) was added followed by a solution oftetrakis(triphenylphosphine)palladium catalyst (5 g, 0.0043 mol) in DME(100 mL). The reaction mixture was stirred at reflux for 2 hours,concentrated and treated with 4N HCl (375 mL) at 5 to 10° C. Isopropanol(1 L) was added to form a suspension that was filtered, washed withisopropanol (3×0.5 L), and dried in a vacuum oven at 50 to 55° C. togive5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-oxo-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrile(91 g, 83.5% yield, purity 98.7% HPLC area).

EXAMPLE 6 PREPARATION OF5-(SPIRO[CYCLOHEXANE-1,3′-[3H]INDOLE]-2′-OXO-5′-YL)-1H-PYRROLE-1-METHYL-2-CARBONITRILE

In this example, a larger scale production of5-(spiro[cyclohexane-1,3′-[3H]indole]-2′-oxo-5′-yl)-1H-pyrrole-1-methyl-2-carbonitrilewas performed using the procedure of Example 5.

5′-Bromospiro[cyclohexane-1,3′-indol]-2′(1′H)-one (7.99 kg, 28.53 mol)was charged and stirred with 1,2-dimethoxyethane (59 kg). To thissolution was added a 16.5% potassium carbonate solution (48 kg, 57 mol).The batch temperature was adjusted to 25° C. and5-[1,3,6,2]dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile (9.46kg, 43.2 mol) and tetrakis(triphenylphosphine)palladium(0) catalyst(0.40 kg, 0.35 mol) were added. The mixture was heated to reflux atabout 80° C. and held at reflux for 2 hours. The solution was thenanalyzed for the presence of starting material and showed 0.9% startingmaterial, indicating completion of the reaction. Most of the solvent wasremoved by atmospheric distillation and the batch was cooled to below10° C. A 4N HCl solution (36 kg) was added to the batch over about 0.5hours while the batch temperature was controlled at 8 to 11° C. To theacidified mixture was charged isopropanol (63 kg) and the batchtemperature was adjusted to about 10° C. The batch was filtered, washedwith isopropanol (31 kg) and blown with nitrogen. The filter cake wasfurther dried in a vacuum oven at 55° C. to furnish 9.63 kg of the crudeproduct.

The crude product (8.61 kg, 28.2 mol) and N-acetyl-L-cysteine (2.21 kg,13.5 mol) were charged with tetrahydrofuran (108 kg). To assure completecomplexing of residual palladium, the solution was stirred overnight at20° C. The batch was clarified through a Celite® pre-coated filter andthen through a 0.2-micron Polypure DCF cartridge filter. The clarifiedsolution was brought to reflux and distilled at ambient pressure until alandmark at 43 L residual volume was reached. The distillationtemperature ranged from 67 to 70° C. To the concentrate was addedisopropanol (68.5 kg) and the distillation resumed to reduce batchvolume to the earlier landmark. The distillation temperature ranged from77 to 83° C. A second aliquot of isopropanol (68 kg) was added and thedistillation repeated at a temperature of 83 to 85° C. The batch wasevaluated for residual solvent analysis by GC to verify THF removal; aTHF/IPA weight ratio of 0.02 was found, confirming that the conditionsensured adequate THF removal. The batch was cooled to 24° C. over 1.2hours. The batch was further cooled to 11° C. and stirred for a minimumof 0.5 hours at the same temperature. The resulting slurry was filtered,the filter cake was washed with isopropanol (13 kg) and blown on thefilter with nitrogen. The wet cake was further dried under vacuum at 50°C. to a constant weight. The dry product weight was 6.50 kg for anoverall yield of 83.5% (99.8% purity by HPLC area, 0.04% largest singleimpurity).

EXAMPLE 7 PREPARATION OF5-(4,4-DIMETHYL-2-OXO-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1H-PYRROLE-2-CARBONITRILE

1-Methylpyrolle-2-carbonitrile (16.5 kg, 1.86 eq.), tri-isopropyl borate(29.3 kg, 1.88 eq.) and THF (88.9 kg) were combined and cooled to −10 to−4° C. LDA (82.0 kg) was added over at least 11 hours while maintainingthe reaction temperature at −2 to 8° C. throughout the addition. Highperformance liquid chromatography (HPLC) was utilized to detectcompletion of the reaction. Once completed, the boronate intermediatewas rinsed with THF (2.96 kg) and the mixture heated to 5 to 11° C.

The Brofoxine™ reagent (21.3 kg, 1.0 eq.), THF (76.9 kg) and a potassiumcarbonate/water solution (22.0 kg; 76.7 kg respectively) were combinedunder an atmosphere of nitrogen. Tetrakis (triphenylphosphine) palladium(0) (0.386 kg, 0.022 eq.) in tetrahydrofuran (11.8 kg) was added to theBrofoxine™ mixture and heated to reflux.

The boronate intermediate was then added to the Brofoxine™ mixture overa period of at least 7 hours at reflux. The reaction was monitored byHPLC and addition of the Brofoxine reagent was ceased when HPLCindicated that the reaction was complete.

The mixture was then rinsed using THF (21.3 kg) and cooled to 19 to 25°C. THF (94.4 kg) and water (157 kg) were added, the mixture stirreduntil all of the solid material dissolved or was suspended, and themixture cooled to 5 to 11° C. The pH of the mixture was adjusted to a pHof 4 to 5 using hydrochloric acid (about 74.0 kg) or sodium hydroxide,which maintaining a temperature of 5 to 15° C. The mixture was rinsedusing water (2.0 kg), then heated to 19 to 25° C. for at least 30minutes with stirring, and then settled for at least 30 minutes.

L-Cysteine (3.55 kg) and THF (10.8 kg) were added to the organic layer,THF (2.0 kg) added, and the mixture heated to 49 to 55° C. for at least12 hours. The L-cysteine was removed by filtration and the filtraterinsed with THF (44.4 kg).

Toluene was then added (144 kg), the mixture concentrated under reducedpressures at a temperature of less than 45° C. to a volume of 121±20liters. A second aliquot of toluene (72.5 kg) was added, the mixtureconcentrated under reduced pressure at a temperature of less than 45° C.to a volume of 121±20 liters. The temperature was adjusted to 19 to 25°C. Heptane (114 kg) was added and the mixture stirred for at least 60minutes. The mixture was the filtered and the filter cake slurried withmethanol (42.6 kg) until the Brofoxine™ reagent was removed. The wetcake was dried at less than 45° C.

EXAMPLE 8 PREPARATION OF5-(4,4-DIMETHYL-2-THIOXO-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-6-YL)-1H-PYRROLE-2-CARBONITRILE

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile(14.5 kg), Lawesson's Reagent (12.1 kg, 1.16 eq.), DME (215 kg), andacetonitrile (8.96 kg) were combined and heated to reflux for at least 4hours at less than 16 hours to form unpurified5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.The mixture was cooled to 18 to 28° C., quenched with water (276 kg),cooled to 10 to 20° C., stirred for at least 30 minutes, and theresulting slurry collected via filtration.

The wet cake was slurried in water (62.3 kg) for at least 2 hours, theslurry collected via filtration, and the wet cake washed with a secondaliquot of water (20.7 kg). The resulting wet solid was dried undernitrogen and vacuum at room temperature for at least 12 hours.

The unpurified5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrilewas then purified by dissolving the product in THF (61.4 kg) at 19 to25° C. until a solution was obtained, which was then cooled to 12 to 18°C. A slurry of potassium-t-butoxide (17.4 kg) and tetrahydrofuran (61.4kg) was then added while maintaining a temperature of 10 to 20° C., THF(30.7 kg) was added, and the mixture stirred at 10 to 20° C. for atleast 60 minutes. The resulting slurry was filtered and the resultantfilter cake washed three times with THF (36.8 kg each).

The filter cake was then dissolved in aqueous acetone (48.3 kg water;38.3 kg acetone) at 19 to 25° C. until a solution was obtained and thesolution cooled to 2 to 8° C. A 10% hydrochloric acid solution (34.7 kgwater; 16.1 kg hydrochloric acid) was then added over at least 80minutes. A temperature of 2 to 8° C. was maintained until a pH of 3 to 5was achieved. The mixture was then stirred at 2 to 8° C. for at least 30minutes and filtered. The filter cake was washed three times with water(18.4 kg each) and dried at less than 45° C.

The dried filter cake was then dissolved in acetone (94.4 kg) and themixture heated to 45 to 51° C. until the solid had dissolved. Thesolution was then filtered through a 10 micron filter, the filter rinsedwith acetone (13.5 kg), and the solution heated to reflux to removeabout 113 liters of acetone by distillation. The concentrated solutionwas then maintained at reflux and water (56.6 kg) was added at a ratewhich maintains reflux. The mixture was then cooled to 2 to 8° C. at arate of not more than 0.5° C. per minute.

The cooled mixture was then stirred at 2 to 8° C. for at least 60minutes and filtered. The filter cake was washed three times withaqueous acetone (3.39 kg water; 2.68 kg acetone each). The washed solidwas pre-dried at less than 35° C. for at least 4 hours and then dried atless than 50° C. to obtain purified5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A method for preparing 2-cyanopyrrole borate salts comprising combining: (a) a boron agent of the formula: (i) B(OR¹)(OR²)(OR³), wherein: R¹, R², and R³ are, independently, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, or substituted C₃ to C₈ cycloalkyl; or (ii). B(R⁴)(R⁵)(R⁶), wherein: R⁴, R⁵, and R⁶ are, independently, halogen, C₁ to C₆ alkyl, or substituted C to C₆ alkyl; (b) a substituted 2-cyanopyrrole of the formula I:

wherein: R⁷ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or COR^(A); R^(A) is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl; Q_(a) is H, OH, NH², CN, halogen, C₁ to C₆ alkyl, substituted C, to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆ aminoalkyl, or COR^(B); a is 0 to 2; R^(B) is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl; and (c) a strong non-nucleophilic base.
 2. A method for preparing 2-cyanopyrrole (i) boronic esters or borinic esters of formulae (A) or (B):

(ii) boron compounds of formulae (C) or (D):

(iii) salts thereof of formulae (E), (F), (G), or (H):

wherein: R¹, R², and R³ are, independently, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, hetero(C₁ to C₆)alkyl, or substituted hetero(C₁ to C₆)alkyl; R⁴, R⁵, and R⁶ are, independently, halogen, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; R⁷ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or COR^(A); Q is OH, NH², CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆ aminoalkyl, or COR^(B); a is 0 to 2; CC⁺ is a countercation; comprising reacting: (b) a boron agent of the formula: (i) B(OR¹)(OR²)(OR³), wherein: and R¹, R², and R³ are, independently, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, hetero(C₁ to C₆)alkyl, or substituted hetero(C₁ to C₆)alkyl; or (ii) B(R⁴)(R⁵)(R⁶), wherein: R⁴, R⁵, and R¹ are, independently, halogen, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; (b) a substituted 2-cyanopyrrole of formula I:

wherein: R⁷ is C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or COR^(A); R^(A) is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl; Q is OH, NH², CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, substituted C₁ to C₆ aminoalkyl, or COR^(B); a is 0 to 2; R^(B) is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl; and (c) a strong non-nucleophilic base.
 3. The method according to claim 2, wherein R¹, R², and R³ are selected from the group consisting of C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, and hetero(C₁ to C₆)alkyl.
 4. The method according to claim 3, wherein R¹, R², and R³ are isopropyl.
 5. The method according to claim 2, wherein said 2-cyanopyrrole is of the structure:


6. The method according to claim 2, wherein said strong non-nucleophilic base is lithium diisopropyl amine.
 7. The method according to claim 2, wherein said 2-cyanopyrrole boronic ester, boronic ester salt, borinic ester, or borinic ester salt is selected from the group consisting of:


8. A method of preparing a boronic or borinic acid comprising hydrolyzing said boronic ester, boronic ester salt, borinic ester, borinic ester salt, or combinations thereof prepared according to claim
 2. 9. The method according to claim 8, wherein said 2-cyanopyrrole boronic or borinic acid is of the formula:


10. A method of preparing a compound of the structure:

wherein: R¹⁸ is 2-cyanopyrrole or substituted 2-cyanopyrrole; R¹⁹ (CR²⁰R²¹) or —(CR²⁰R²¹), —N(R²²)—(CR²⁰R²¹)_(t)—; s is 1 to 5; t is 1 to 5; R²⁰ and R²¹ are, independently, H, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; and R²² is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, or substituted aryl; said method comprising reacting said boronic acid prepared according to claim 8 with a glycol of the formula HO—(CR²⁰R²¹), —OH or alkanolamine of the structure HO—(CR²⁰R²¹)_(s)—N(R²²)—(CR²⁰, R²¹)_(t)—OH.
 11. The method according to claim 10, wherein R¹⁸ is N-methyl-2-pyrrole carbonitrile and R¹⁹ is —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, —C(CH₃)₂CH(CH₃)—, or —C(CH₃)₂C(CH₃)₂—.
 12. A method for preparing 2-cyanopyrrole trifluoroborate salts comprising adding potassium hydrogen fluoride to said boronic ester, borinate ester, or salt prepared according to claim
 2. 13. The method according to claim 12, wherein said 2-cyanopyrrole trifluoroborate salt is of the formula:


14. A method for coupling a 2-cyanopyrrole and an aromatic compound to give a 2-cyanopyrrol-5-yl substituted aromatic compound-, comprising reacting the product of claim 2 with an aromatic compound and an organometallic coupling agent.
 15. The method according to claim 14, wherein said aromatic compound is of the structure:

wherein: R⁸ and R⁹ are, independently, H, C₁ to C₆ alkyl, or substituted C₁ to C₆ alkyl; or R⁸ and R⁹ are fused to form: (iii) a saturated 3 to 8 membered spirocyclic ring; (iv) a 3 to 8 membered spirocyclic ring having in its backbone at least 1 carbon-carbon double bond; or (v) a 3 to 8 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S and N; the rings of (iii), (iv) and (v) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆ thioalkyl, CF₃, OH, CN, NH², NH(C₁ to C₆ alkyl), and N(C₁ to C₆ alkyl)₂; R¹⁰ is H, OH, NH², CN, halogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, or CORD; R^(D) is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C, to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl; R¹¹ is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl; L is halogen, triflate, or a diazonium salt; G is O, S, or absent; D is O, S, NR¹², or CR¹³R¹⁴; R¹² is selected from the group consisting of CN, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, SO₂CF₃, OR¹⁵ and NR¹⁵R⁶; R¹³ and R¹⁴ are independent substituents selected from the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, NO₂, CN, and CO₂R¹⁷; R¹⁵ and R¹⁶ are independently selected from the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and sulfonyl; R¹⁷ is C₁ to C₃ alkyl; or CR¹³R¹⁴ is a six membered ring as shown by the structure below:

or a pharmaceutically acceptable salt thereof.
 16. A method for preparing 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile comprising: (a) reacting 1-methyl-pyrrole-2-carbonitrile and a boron agent as defined in claim 1; (b) reacting the product of step (a) with 6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; and (c) reacting the product of step (b) with Lawesson's reagent.
 17. A method for preparing purified 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile comprising: (a) reacting 1-methyl-pyrrole-2-carbonitrile, lithium di-isopropylamide and tri-isopropylborate; (b) reacting the product of step (a) with 6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, potassium carbonate, and a soluble palladium (0) catalyst; (c) washing the 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile with water and THF; (d) adjusting the pH of the product of step (c) to 4 to 5; (e) adding L-cysteine to the product of step (d); (f) removing excess cysteine; (g) exchanging the first solvent for toluene; (h) precipitating the product of step (g); and (i) drying the purified 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile.
 18. A method of preparing 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile comprising reacting said purified 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile of claim 17 and Lawesson's reagent.
 19. The method according to claim 18, further comprising: (a) forming a salt of 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile; (b) acidifying the product of step (a); (c) dissolving the product of step (b) in acetone; (d) precipitating the product of step (c); and (e) drying the product of step (d).
 20. The method according to claim 19, wherein step (a) is performed with potassium t-butoxide.
 21. A product prepared according to the method of claim
 2. 22. A compound selected from the group consisting of (5-cyano-1-methyl-1H-pyrrol-2-yl) boronic acid, (5-cyano-1-methyl-1H-pyrrol-2-yl) trifluoroborate potassium salt, 5-[1,3,6,2]Dioxazaborocan-2-yl-1-methyl-1H-pyrrole-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
 23. A container comprising the compound of claim
 22. 